Ifosfamide ±VP16 in Childhood' Malignancy

all to patients receiving additional VP16. Nadir neutrophil counts fell below 0.5x109/L in 42% of the single agent group and 69% of the two agent group. There were no documented bacteraemias. Nadir platelet count fell below 50x109/L in 6 cases (combined therapy); only one platelet transfusion was required, for a minor bleeding episode. There were no episodes of frank haematuria. The higher dose of MESNA did not confer protection against microscopic haematuria. Emesis occurred in all but two patient courses, but was considered of comparable severity to other non-platinum containing regimens. Two patients had a generalized convulsion, both with full recovery. There was no demonstrable renal or hepatic toxicity. We conclude that these regimens have acceptable toxicity in the context of the high risk patients treated and the alternative available treatment options.


INTRODUCTION
Alkylating agents are of major importance in the treatment of malignant solid tumours in childhood. The efficacy and toxicity of one such agent, cyclophosphamide (an oxazophorine) have been widely reported. Ifosfamide, another drug of the oxazophorine class, has been shown to be active against a wide range of human malignancies in both adults and children. There is evidence to suggest that Ifosfamide and Cyclophosphamide have significant differences in their modes of action, spectrum of activity and toxicity (1). Phase II trials using ifosfamide began in the early 1970's but its use was restricted until recently by the major dose-limiting sideeffect of urothelial toxicity. Recent studies have shown that the thiol compound Sodium 2 mercaptoethane sulphonate (MESNA) protects the urothelium from the toxic effects associated with high dose oxazophorine therapy, probably by combining with and inactivating their toxic metabolites, particularly acrolein.
Since November 1983, Ifosfamide has been incorporated in some of our first-line chemotherapeutic regimens in the treatment of solid malignancies of childhood. This paper reports the toxicity experienced in the first thirty children treated by us with Ifosfamide (92 courses) when used bottT'as a single agent and in combination with the epipodophyllotoxin VP16(213) ( Table 1). The response rates to these regimens will be reported elsewhere.   a) Anaemia?Four courses were unevaluable due to lack of data and 4 because of transfusions given at the time of chemotherapy (Table 4). Packed red cells were generally administered if the nadir haemoglobin concentration fell below 8G/dl. No patient receiving regimens A or B required transfusions, but they were required following 9 of 30 ?valuable courses of regimen C and 1 of 11 evaluable courses of regimen D. b) Neutropaenia?The nadir neutrophil counts (x109/ 1) are shown in Table 5. A significant pyrexia (temperatures>38.5?C) associated with neutropaenia (<1 x109/1) occurred after only 4 courses; 3 of regimen C and 1 of regimen A. All 4 remained culture negative and became afebrile on our standard iv antibiotic regimen (Cefuroxime and Tobramycin) with 4 days. c) Thrombocytopaenia?Significant nadir platelet counts (<100x109/1) are shown in Table 6. There was only one significant bleeding episode (epistaxis associated with thrombocytopaenia) on regimen C, which rapidly resolved following platelet transfusion. d) Delay?Myelosuppression resulted in delay of the next course of chemotherapy in only 7 of 88 evaluable courses ( Table 7) 5 following regimen C (26-33 days and one each following regimens B and D. (Table 8) 4 courses were unevaluable due to insufficient data.

Haematuria
No frank or gross haematuria was observed throughout the study. Microscopic haematuria was found as detailed in the table.
3. Other Toxicity a) neurological: Two patients experienced generalized tonic-clonic convulsions whilst receiving chemotherapy, but recovered fully with no apparent sequelae. Chemotherapy was repeated in both patients using the same drugs/dosages without further seizure activity. Plasma electrolytes, osmolality,   c) A single episode of Radiation Recall occurred in a patient treated with regimen C for Ewings Sarcoma of the scapula. This was of mild/moderate severity with moderate skin erythema and desquamation but with full subsequent recovery. d) No clinical or biochemical renal or hepatic toxicity was documented. There were no instances of significant hypotension due to VP16 or coagulation disorders as reported by others (1).

DISCUSSION
Ifosfamide is now established as a first line agent in the treatment of paediatric malignancies. Encouraging results have been obtained in the treatment of poor prognostic sarcomas such as Ewings Sarcoms and advanced Rhabdomyosarcoma (2,3). It is incorporated in current West German and UKCCSG Ewings Sarcoma Trials and the SIOP and Italian Rhabdomyosarcoma Trials. Ifosfamide is also active against other tumours such as advanced or relapsed Wilms Tumour (3,4) and Osteosarcoma (2,3). Responses have been documented in a number of tumours refractory to cyclophosphamide therapy (2,3,4). Our own experience with ifosfamide therapy is similar and will be reported elsewhere. It remains to be seen whether ifosfamide is superior to cyclophosphamide in randomised trials in the treatment of paediatric solid tumours, although preliminary results from a European trial comparing these two agents for adult sarcomass, favour ifosfamide (5).
In this toxicity study, Ifosfamide plus MESNA was well tolerated at a dose of 6 gm/m2, either as a single agent or combined with VP16(213). Although neutrophil counts fell below 0.5x109/L after 56% of courses, there were only 4 (4.2%), instances of febrile neutropaenia and no demonstrable bacteraemias. Only 8% of subsequent chemotherapy courses were delayed due to myelosup' pression. The introduction of regional detoxification with MES-NA has ameliorated the hitherto dose-limiting urothelial toxicity. In animal models Habs and Schmahl were able to show that MESNA offered a protective effect against oxazophorine-induced bladder cancer (6). We chose a regimen for MESNA as a 24 hour infusion of either 100% or 150% of the Ifosfamide dosage, pre' ceeded by a relative dose of 16.7% or 25% as a bolus- The MESNA and Ifosfamide infusion was followed by four further boluses totalling 75% or 100% of the Ifosfa* mide dosage. Post-infusion MESNA boluses were given 3 hourly in contrast to the more usual 4-hourly regimen on discussions with the manufacturers and following the report of Link et al (7). The absence of haematuria recorded in this series is consistent with the findings of Pinkerton et al (4) and Magrath (2), but De Kraker and Voute reported a 16% incidence of frank haematuria using 130% of the total Ifosfamide dosage given as 4-hourly boluses (3). The higher dose of MESNA in our study did not afford protection from microscopic haematuria.
Two generalized convulsions occurred as reported bV others (3,4). This appears to be an idiosyncratic phe' nomenon of uncertain causation. It has been suggested that MESNA could be responsible for promoting seizure activity, but more recent work has implicated toxic Ifosfamide metabolites. We and others (3,4) were able to administer further Ifosfamide to patients experiencing convulsions without further seizure activity. The optimum method of ifosfamide administration's not yet established. Further studies are required to compare short and prolonged infusions and to determine whether regimens spread over several days confer an advantage. Larger scale trials are required to define the role of ifosfamide in the treatment of paediatric mali9' nancy and to determine whether it is superior to cyc' lophophamide. Initial reports however with respect to both efficacy and toxicity seem encouraging and justify randomised trials in which it is used as an agent of first choice in comparison to its more established congener cyclophosphamide.